Radiation therapy is one of the widespread and effective treatment modalities for cancer patients. Despite demonstrated advantages, there are some drawbacks of radiotherapy including, normal tissue damage, and radiation tolerance of tumors. The outcome of the radiation treatment is primarily determined by the radiosensitivity of tumor cells. Much attention has been focused on studying the molecular machinery behind radiation tolerance or radioresistance of tumors. A commonly studied target is heat shock proteins.
Heat shock proteins (Hsp) are well described molecular chaperones that are intricately involved in the folding, stability, activation and maturation of key proteins involved in the cell cycle and signal transduction. Hsp90 and 70 are perhaps the best studied chaperones in the heat shock family that have been linked to cancer.
Hsp70 is responsible for helping in the natural cycle of protein folding post ribosomal production, assisting improperly folded proteins (either naturally or from external stresses such as hyperthermia) to either realize their optimal tertiary folded conformation, to facilitate protein sequestration, and to regulate protein degradation. This protein maintenance function is highly important because if damaged proteins are not either selectively refolded to regain functioning or degraded they will begin to accumulate in the cytosol effectively interfering with established signaling pathways thereby clogging the cellular mechanisms inducing apoptosis.
The expression of Hsp90 is known to be up-regulated in malignant type compared to the normal tissues. Many Hsp90 client proteins are known to be involved in cancer metastasis, invasion, and angiogenesis. Hsp90 stabilizes proteins such as, Raf-1, Akt and ErbB2 that promote cellular survival by protecting from radiation induced cell death. Inhibition of Hsp90 causes inactivation of these client proteins increasing tumor cell death in numerous cell lines and tumor models. A variety of Hsp90 inhibitors have been reported and demonstrated the inhibitory effects of enhancing radiosensitivity in various histologies. However, research has shown that inhibition of Hsp90 typically causes up-regulation of Hsp70, ultimately limiting the outcome of Hsp90 inhibition for cancer cell death.